BIOCHEMICAL TOXICOLOGY AND MOLECULAR STRESS RESPONSES

环境化学品对人类和其他生物有多种毒性作用。 包括器官衰竭、出生缺陷和癌症在内的有机体， 由复杂的分子和生化信号模式引发。 给定 成千上万的环境毒素，很难确定一个 作用机制或确定这些反应的病原体。 然而，很明显，生物后果是由于 毒素或代谢物与细胞组分的相互作用。 虽然细胞中毒素的靶点很多，但对许多细胞的损害 不同的靶点可引起常见的毒性生化机制， 例如，Ca 2+稳态改变、谷胱甘肽和氧化还原酶耗竭 压力，这将损害与细胞死亡联系起来。因此，多效性 对化学毒素的反应可能与少量的 生化事件 基因表达的变化是对环境毒素的常见反应， 并可用于调节导致多效性的早期事件， 生物反应。最常见的被激活的基因 化学毒素是应激反应基因如热休克蛋白， 葡萄糖调节蛋白和转录激活因子。是 这些分子应激反应可能与 毒性或保护的发展。我们的长期目标是 确定压力基因表达的变化是否代表了 调节对毒素的生物反应。具体假设 要测试的是，“压力表达增加的信号 应答基因与介导细胞毒性的信号重叠， 不同种类的化学毒素“我们将使用一个特征良好的 细胞毒性模型、LLC-PK 1细胞和三种不同毒素， 碘乙酰胺、叔丁基过氧化氢和肾毒性半胱氨酸缀合物， 来验证这个假设3应激反应的激活机制 基因（hsp 70，grp 78和gadd 153）由所有三种毒素将比较， 确定共同的转录和转录后信号传导 机制存在。 我们还将开始研究， 毒素抵抗力差异的基础。我们希望 阐明这些基本的分子反应将使我们能够更好地 了解导致生物反应的事件级联 化学毒素。

Environmental chemicals have pleotropic toxic effects on humans and other organisms including organ failure, birth defects and cancers, which are elicited by a complex pattern of molecular and biochemical signals. Given the thousands of environmental toxins, it can be difficult to determine a mechanism of action or to identify -causative agents for these responses. However, it is clear that the biological consequences are due to the interaction of the toxin, or a metabolite, with components of the cell. Although there are many targets for toxins in a cell, damage to many different targets may elicit common biochemical mechanisms of toxicity, e.g. altered Ca2+ homeostasis, depletion of glutathione and oxidative stress, which couple the damage to cell death. Therefore, the pleotropic responses to chemical toxins may be linked by a smaller number of biochemical events. A change in gene expression is a common response to environmental toxins, and may serve to regulate early events which lead to the pleotropic biological responses. The most common genes which are activated by chemical toxins are stress response genes such as heat shock proteins, glucose regulated proteins and transcription activating factors. It is possible that these molecular stress responses are involved either in development of toxicities, or protection. Our long term goal is to determine if changes in stress gene expression represent common points of regulation for the biological response to,toxins. The specific hypothesis to be tested is, "The signals for increased expression of stress responsive genes overlap with the signals which mediate cytotoxicity for different classes of chemical toxins." We will use a well characterized cell model of toxicity, LLC-PK1 cells, and three different toxins, iodoacetamide, t-butylhydroperoxide and nephrotoxic cysteine conjugates, to test this hypothesis. Mechanisms for activation of 3 stress responsive genes (hsp7O, grp78 and gadd153) by all three toxins will be compared to determine if common transcriptional and posttranscriptional signalling mechanisms exist. We will also begin studies to determine the genomic basis for differences in resistance to toxins. Our hope is that elucidating these fundamental molecular responses will allow us to better understand the cascade of events which result in the biological response to chemical toxins.